About Epimacular Brachytherapy

Strontium 90 for the treatment of wet AMD

Localised radiation treatment has the ability to prevent proliferation of vascular tissue by inhibiting neovascularisation. After low-dose radiation, vascular endothelium demonstrates morphologic and DNA changes, inhibition of replication, increased cell permeability, and apoptosis. Fibroblast proliferation and subsequent scar formation, a hallmark of end-stage neovascular AMD, are also inhibited.

Choroidal neovascularisation (CNV) membranes, which contain endothelial cells that are proliferating due to the hypoxic environment and the chemokines that are produced, are more sensitive to radiation treatment than the retinal vasculature and non-proliferating capillary endothelial cells and larger vessels.

The epimacular brachytherapy device* used for the treatment of CNV associated with AMD offers potential advantages over standard radiation treatment and laser photocoagulation. In contrast to external beam radiotherapy, a larger dose can be delivered to the macula with less irradiation of normal ocular structures and surrounding tissues. And unlike laser photocoagulation, in which laser energy is used to coagulate the CNV membranes, there is no thermal injury to the retina or injury to the surrounding tissues since the epimacular brachytherapy applicator is selective to proliferating cells and tissues.

* Epimacular brachytherapy (VIDION® System) is manufactured by NeoVista Inc. in the US and distributed in the UK by Carleton Ltd

Supporting evidence for Strontium 90 in the treatment of CNV associated with wet AMD

Jaakkola et al 2005 A prospective controlled study of 86 subjects reported on the use of external strontium 90 plaque with single doses of 15 Gy and 12.6 Gy. Recent re-calibration measurements have revealed that the actual dose delivered by Plaque I was 32.4 Gy instead of 15 Gy [NVI-0093]. The recalibration was performed by two groups, STEP/AEA-QSA and STUK (Finnish Center for Radiation and Safety)]. The same calibration experiments confirmed the published dose of Plaque II as 12.6 Gy. The 32.4 Gy group demonstrated significantly more favourable visual acuity results as compared with the control group. The control group lost an average of 3.02, 3.95, and 4.90 lines at 6, 12, and 24 months, respectively; while the treated group lost 0.24, 0.82, and 2.41 lines. The 12.6 Gy group did not show a significant difference compared to the control, suggesting the higher dose is more effective. Neither treatment group differed significantly from controls at 36 months. Angiographically, in both treatment groups combined, the CNV was considered less active than at baseline in 76.9% of the treated subjects at 6 months, 77.1% at 12 months, and 75.0% at 24 months, compared with 43.2%, 71.4%, and 78.4% at 6, 12, and 24 months respectively. The macula was considered clinically dry in 37.5% of the treated subjects at 6 months, 56.4% at 12 months, and 43.6% at 24 months, compared to 2.3%%, 21.1%, and 31.3% at 6, 12, and 24 months respectively.
Jaakkola et al 1998 In another study by Jaakkola et al, strontium 90 Plaque I was evaluated in a prospective, non-randomised clinical trial. A single dose of 29 Gy at a depth of 1.75 mm was used (see explanation of calibration experiments above). The applicator was surgically introduced in the episcleral surface, under the macula and held in place manually for the treatment period of 54 minutes. Twenty subjects with recently diagnosed CNV received plaque applicator treatment and 12 subjects were followed as controls. At 12 months follow-up, 3 (15%) of the 20 Strontium 90 treated eyes experienced a decrease of six or more lines of visual acuity, as compared to 6 (50%) of the 12 non-treated eyes (p=0.057). The mean number of lines lost was 2.6 (SD 3.7) for treated eyes and 5.3 (SD 3.2) in non-treated eyes (p=0.024). No radiation-related adverse effects were noted.
Finger et al 1999 Ophthalmic plaque (palladium 103 using 1250 to 2362 cGy) therapy was used to treat 23 eyes of 23 subjects. Subjects were followed for a mean of 19 months (S.D. 10.7 months, range 3 to 37 months). Six months after treatment, three (16%) of 19 eyes had lost three or more lines of best-corrected visual acuity. In the 13 eyes examined 12 months after treatment, four eyes (31%) lost three or more lines of acuity, and 24 months after radiation therapy, only two (22% of nine eyes) lost three or more lines of visual acuity. No eye suffered sudden irreversible loss of central vision. No radiation retinopathy, optic neuropathy, or cataract could be attributed to radiotherapy within this follow-up period.

The absence of reports of radiation retinopathy, optic neuropathy, or cataract formation attributable to use of strontium 90 in these published studies of ocular plaque strontrium 90 used in the management of subretinal CNV is consistent with the safety profile of strontrium 90 for use in the treatment of ocular tumors.

These findings support the clinical evaluation of Sr90 in the management of CNV proposed in this clinical study protocol.

Supporting evidence for epiretinal brachytherapy in the treatment of wet AMD

 

Efficacy

Study data patients followed up for 12 months following treatment with epimacular brachytherapy (using the anti-VEGF drug bevacizumab; ranibizumab was not available at the time of this study) is available for 34 treatment-naïve patients [Avila et al 2009; NVI-111 study]. Data from the same patients followed up for 18 months has been presented and discussed at various congresses by Kuppermann and Dessouki.

The objective of the NVI-111 study was to evaluate the safety and feasibility of concomitant treatment with epimacular brachytherapy and anti-VEGF in patients with wet AMD. Eligibility criteria for this study was:

This study was conducted in treatment-naïve patients and, as such, patients were given one anti-VEGF injection at the time of surgery and another 1 month later. Further injections were given on a prn basis, dependent on the physician’s assessment of disease activity.

Analysis at 12 months follow-up showed:

This is comparable to 12 month outcome data for ranibizumab, in which 94% and 96% of patients lost 15 letters or fewer in the MARINA and ANCHOR trials respectively. Both ANCHOR and MARINA used a monthly treatment regimen. NICE guidance follows a prn regimen similar to the PrONTO study, which reported a mean gain of 9.3 ETDRS letters, 35% vision gain (15 or more letters), and 95% vision maintenance (lost 15 letters or fewer) using the same outcome definitions as the NVI-111. Patients in the PrONTO study required an average of 5.6 ranibizumab injections by month 12, compared with patients in the NVI-111, who required an average total of 2.4 injections of anti-VEGF treatment.

Twelve-month data from the NVI-111 study presented by Brown at the American Society of Retina Specialist’s (ASRS) 26th Annual Meeting, 2008 demonstrated anatomic improvements on both FFA and OCT.2 This improvement was in respect to resolved fluid on OCT and a decrease in FFA with respect to the lesion size.

An on-going randomised multicentre, multi-national study (CABERNET) of over 400 patients is investigating epimacular brachytherapy with concomitant ranibizumab. FDA review showed no unexpected safety concerns and recruitment has reached the midpoint.

 

Safety

Patients treated with strontium-90 delivered in significantly higher doses (up to 2,000 cGy) than in the epimacular brachytherapy procedure described here (24 Gy dosage), showed no acute or late morbidity, even after 3 or more years.[Smith et al, Parvani et al, Wesberry et al]

In the NVI-111 study, most of the limited number of adverse events were related to the vitrectomy procedure, or the underlying disease process, rather than the epimacular brachytherapy (Table).

To date, data is available for 68 patents who have been treated by epimacular brachytherapy in 2 trials (NVI-068 and NVI-111), and no instances of radiation toxicity have been observed.

 

Cataract

25%

(6/24)

Epimacular membrane

3%

(1/34)

Retinal tear

3%

(1/34)

Subretinal hemorrhage (mild)

3%

(1/34)

Subretinal fibrosis

6%

(2/34)

Radiation retinopathy

0%

(0/34)

 

Concomitant treatment with epimacular brachytherapy and the anti-VEGF drug bevacizumab (study NVI-111) – Adverse events at 12 months

Device description

The epimacular brachytherapy system* used in the MERLOT study is an intraocular Strontium 90 applicator device intended to treat neovascularisation of retinal tissue by means of local, directional delivery of radiation to target tissues.

VIDION
Vidion® System (Image courtesy NeoVista Inc.)

Using standard vitreoretinal surgical techniques, the sealed radiation source is placed temporarily over the fovea in the vitreous cavity by means of a proprietary intraocular probe.

When in the storage (retracted) position, the radiation source is surrounded by materials designed to effectively protect the surgeon, staff, and subject during the handling and initial positioning. During treatment (source engaged), the source is located within a specially designed stainless steel tip that allows the radiation to reach the target tissues while the source is contained in a closed system. This local, focused delivery may allow for the treatment benefits of radiation with less toxicity to surrounding tissues.

Epimacular brachytherapy (VIDION® System) is manufactured by NeoVista Inc. in the US and distributed in the UK by Carleton Ltd

Radiation dose characterisation

The device design optimises the radiation dose curves to deliver therapeutic dosage to the CNV while protecting other critical ocular structures. Based on a target dose of 24 Gy at the peak of the distribution, Table 1 estimates the dose received by the lens, optic disc, optic nerve, and retina during treatment.

Table 1
Radiation Dose Received By Critical Structures

Structure

Maximum Dose

Estimated distance from target (i.e., fovea)*

Shortest distance to probe surface at source center
(considering probe dimensions)

Lens

0.56 mGy

>15 mm
from choroid to posterior aspect of the lens

11.7 mm

Optic disc (closest edge)

6.3 Gy

3 mm
optic disc edge to foveal center

3.6 mm

Optic nerve

2.4 Gy

3.1 mm

3.6 mm

Retina – fovea

24 Gy

within a 1.5 mm diameter 

Retina – macula

23 Gy

within an annulus 1.5 to 6.0 mm diameter

Retina - peripheral

8 Gy

Outside a 6.0 mm diameter circle

*Distance estimates based on Jakobiec FA and Ozanics V, General topographic anatomy of the eye, in Duane’s Foundations of Clinical Ophthalmology, Tasman W and Jaeger EA, Eds. 1999

 

The radiation dosimetry of the treatment area is characterised in Figure 2 below.

Figure 1
line graph
DOSE RATE PROFILE OF DELIVERY DEVICE

References

Jaakkola A, Heikkonen J, Tommila P, Laatikainen L, Immonen I. Strontium Plaque Brachytherapy for Exudative Age-Related Macular Degeneration: Three-Year Results of a Randomized Study. Ophthalmology 112[4], 2005; 567-573.28

Jaakkola A, Heikkonen J, Tommila P, Laatikainen L, Immomen I. Strontium plaque irradiation of subfoveal neovascular membranes in age-related macular degeneration. Graefes Arch.Clin.Exp.Ophthalmol. 1998; 236:24-30.

Finger PT, Berson A, Ng T, Szechter A. Ophthalmic plaque radiotherapy for age-related macular degeneration associated with subretinal neovascularization. Am J Ophthalmol 1999; 127:170-177.

Avila MP, Farah ME, Duprat JP et al. Twelve month short-term safety and visual acuity results from a multicentre prospective study of epiretinal strontium-90 brachytherapy with bevacizumab for the treatment of subfoveal choroidal neovascularisation secondary to age-related macular degeneration. Br J Ophthalmol. 2009; 93: 305-309.

Kuppermann BD. Epimacular brachytherapy for the treatment of choroidal neovascularization associated with age related macular degeneration. Presented at the Retina sub-specialty meeting, AAO, 2008.

Dessouki A. Focal Epimacular Brachytherapy for the Treatment of CNV.  Meeting presentation.

[MARINA] Rosenfeld PJ for the MARINA Study Group. Ranibizumab for neovascular age-related macular degeneration. N Engl J Med 2006; 355: 1419-31

[ANCHOR] Brown DM for the ANCHOR Study Group. Ranibizumab versus verteporfin for neovascular age-related macular degeneration. N Engl J Med 2006; 355:1432-44

[PrONTO] Spaide R. Ranibizumab according to need: a treatment for age-related macular degeneration. Am J Ophthalmol. 2007;143:679-680

Brown DM. Epimacular brachytherapy and bevacizumab for wet AMD – NVI 111 anatomic outcomes. Abstracted presented at the American Society of Retina Specialist’s (ASRS) 26th Annual Meeting. Maui, Hawai, October 2008

Smith RA et al. Postoperative beta irradiation for control of pterygium. J Miss State Med Assoc. 2001;42:167-9

Parvani SB et al. Management of pterygium with surgery and radiation therapy. The North Florida Pterygium Study Group. Int J Radiat Oncol Biol Phys. 1994;28:101-3.

Wesberry JM Jr., Wesberry JM Sr. Optimal use of beta irradiation in the treatment of pterygia. South Med J. 1993;86:633-7